The Experts below are selected from a list of 312 Experts worldwide ranked by ideXlab platform
A L Svensson - One of the best experts on this subject based on the ideXlab platform.
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Tacrine interacts with different sites on Nicotinic Receptor subtypes in SH-SY5Y neuroblastoma and M10 cells
Behavioural Brain Research, 2000Co-Authors: A L SvenssonAbstract:Abstract The effect of chronic treatment with the cholinesterase inhibitor tacrine on Nicotinic Receptor subtypes was investigated in human SH-SY5Y neuroblastoma cells and in a fibroblast cell line (M10 cells) stably transfected with α4β2 Nicotinic Receptors. Tacrine significantly increased the number of Nicotinic Receptors in SH-SY5Y cells, in a concentration dependent manner (10 −9 to 10 −4 M), when using [ 3 H]epibatidine as labelled ligand. Chronic tacrine treatment of M10 cells significantly increased and decreased the number of α4β2 Nicotinic Receptors in a concentration dependent manner (10 −9 to 5×10 −6 M and 2×10 −5 to 10 −4 M, respectively). The tacrine induced increase of Nicotinic Receptors in SH-SY5Y cells, was not blocked in the presence of the Nicotinic antagonists tubocurarine or mecamylamine. A further increase in the number of Nicotinic Receptors was, however, observed in the presence of mecamylamine. This study demonstrates that the effect of tacrine on the number of Nicotinic Receptor subtypes is different in human SH-SY5Y neuroblastoma and M10 cells. The up-regulation of different Nicotinic Receptor subtypes obtained with tacrine might be achieved through interaction via different binding sites on the Receptor, i.e. the acetylcholine binding site as well as an allosteric site.
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Tacrine interacts with different sites on Nicotinic Receptor subtypes in SH-SY5Y neuroblastoma and M10 cells.
Behavioural brain research, 2000Co-Authors: A L SvenssonAbstract:The effect of chronic treatment with the cholinesterase inhibitor tacrine on Nicotinic Receptor subtypes was investigated in human SH-SY5Y neuroblastoma cells and in a fibroblast cell line (M10 cells) stably transfected with alpha4beta2 Nicotinic Receptors. Tacrine significantly increased the number of Nicotinic Receptors in SH-SY5Y cells, in a concentration dependent manner (10(-9) to 10(-4) M), when using [3H]epibatidine as labelled ligand. Chronic tacrine treatment of M10 cells significantly increased and decreased the number of alpha4beta2 Nicotinic Receptors in a concentration dependent manner (10(-9) to 5 x 10(-6) M and 2 x 10(-5) to 10(-4) M, respectively). The tacrine induced increase of Nicotinic Receptors in SH-SY5Y cells, was not blocked in the presence of the Nicotinic antagonists tubocurarine or mecamylamine. A further increase in the number of Nicotinic Receptors was, however, observed in the presence of mecamylamine. This study demonstrates that the effect of tacrine on the number of Nicotinic Receptor subtypes is different in human SH-SY5Y neuroblastoma and M10 cells. The up-regulation of different Nicotinic Receptor subtypes obtained with tacrine might be achieved through interaction via different binding sites on the Receptor, i.e. the acetylcholine binding site as well as an allosteric site.
Françoise Chesney - One of the best experts on this subject based on the ideXlab platform.
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SSR180711, a Novel Selective α7 Nicotinic Receptor Partial Agonist: (1) Binding and Functional Profile
Neuropsychopharmacology, 2007Co-Authors: Bruno Biton, Olivier E Bergis, Frédéric Galli, Alain Nedelec, Alistair W Lochead, Samir Jegham, Danielle Godet, Christophe Lanneau, Raphaël Santamaria, Françoise ChesneyAbstract:In this paper, we report on the pharmacological and functional profile of SSR180711 (1,4-Diazabicyclo[3.2.2]nonane-4-carboxylic acid, 4-bromophenyl ester), a new selective α 7 acetylcholine Nicotinic Receptor (n-AChRs) partial agonist. SSR180711 displays high affinity for rat and human α 7 n-AChRs ( K _i of 22±4 and 14±1 nM, respectively). Ex vivo ^3[H] α -bungarotoxin binding experiments demonstrate that SSR180711 rapidly penetrates into the brain (ID_50=8 mg/kg p.o.). In functional studies performed with human α 7 n-AChRs expressed in Xenopus oocytes or GH4C1 cells, the compound shows partial agonist effects (intrinsic activity=51 and 36%, EC_50=4.4 and 0.9 μM, respectively). In rat cultured hippocampal neurons, SSR180711 induced large GABA-mediated inhibitory postsynaptic currents and small α -bungarotoxin sensitive currents through the activation of presynaptic and somato-dendritic α 7 n-AChRs, respectively. In mouse hippocampal slices, the compound increased the amplitude of both glutamatergic (EPSCs) and GABAergic (IPSCs) postsynaptic currents evoked in CA1 pyramidal cells. In rat and mouse hippocampal slices, a concentration of 0.3 μM of SSR180711 increased long-term potentiation (LTP) in the CA1 field. Null mutation of the α 7 n-AChR gene totally abolished SSR180711-induced modulation of EPSCs, IPSCs and LTP in mice. Intravenous administration of SSR180711 strongly increased the firing rate of single ventral pallidum neurons, extracellularly recorded in anesthetized rats. In microdialysis experiments, administration of the compound (3–10 mg/kg i.p.) dose-dependently increased extracellular acetylcholine (ACh) levels in the hippocampus and prefrontal cortex of freely moving rats. Together, these results demonstrate that SSR180711 is a selective and partial agonist at human, rat and mouse α 7 n-AChRs, increasing glutamatergic neurotransmission, ACh release and LTP in the hippocampus.
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SSR180711, a Novel Selective α7 Nicotinic Receptor Partial Agonist: (1) Binding and Functional Profile
Neuropsychopharmacology, 2007Co-Authors: Bruno Biton, Olivier E Bergis, Frédéric Galli, Alain Nedelec, Alistair W Lochead, Samir Jegham, Danielle Godet, Christophe Lanneau, Raphaël Santamaria, Françoise ChesneyAbstract:In this paper, we report on the pharmacological and functional profile of SSR180711 (1,4-Diazabicyclo[3.2.2]nonane-4-carboxylic acid, 4-bromophenyl ester), a new selective α 7 acetylcholine Nicotinic Receptor (n-AChRs) partial agonist. SSR180711 displays high affinity for rat and human α 7 n-AChRs ( K _i of 22±4 and 14±1 nM, respectively). Ex vivo ^3[H] α -bungarotoxin binding experiments demonstrate that SSR180711 rapidly penetrates into the brain (ID_50=8 mg/kg p.o.). In functional studies performed with human α 7 n-AChRs expressed in Xenopus oocytes or GH4C1 cells, the compound shows partial agonist effects (intrinsic activity=51 and 36%, EC_50=4.4 and 0.9 μM, respectively). In rat cultured hippocampal neurons, SSR180711 induced large GABA-mediated inhibitory postsynaptic currents and small α -bungarotoxin sensitive currents through the activation of presynaptic and somato-dendritic α 7 n-AChRs, respectively. In mouse hippocampal slices, the compound increased the amplitude of both glutamatergic (EPSCs) and GABAergic (IPSCs) postsynaptic currents evoked in CA1 pyramidal cells. In rat and mouse hippocampal slices, a concentration of 0.3 μM of SSR180711 increased long-term potentiation (LTP) in the CA1 field. Null mutation of the α 7 n-AChR gene totally abolished SSR180711-induced modulation of EPSCs, IPSCs and LTP in mice. Intravenous administration of SSR180711 strongly increased the firing rate of single ventral pallidum neurons, extracellularly recorded in anesthetized rats. In microdialysis experiments, administration of the compound (3–10 mg/kg i.p.) dose-dependently increased extracellular acetylcholine (ACh) levels in the hippocampus and prefrontal cortex of freely moving rats. Together, these results demonstrate that SSR180711 is a selective and partial agonist at human, rat and mouse α 7 n-AChRs, increasing glutamatergic neurotransmission, ACh release and LTP in the hippocampus.
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ssr180711 a novel selective α 7 Nicotinic Receptor partial agonist 1 binding and functional profile
Neuropsychopharmacology, 2007Co-Authors: Bruno Biton, Olivier E Bergis, Frédéric Galli, Alain Nedelec, Alistair W Lochead, Samir Jegham, Danielle Godet, Christophe Lanneau, Raphaël Santamaria, Françoise ChesneyAbstract:In this paper, we report on the pharmacological and functional profile of SSR180711 (1,4-Diazabicyclo[3.2.2]nonane-4-carboxylic acid, 4-bromophenyl ester), a new selective α7 acetylcholine Nicotinic Receptor (n-AChRs) partial agonist. SSR180711 displays high affinity for rat and human α7 n-AChRs (Ki of 22±4 and 14±1 nM, respectively). Ex vivo 3[H]α-bungarotoxin binding experiments demonstrate that SSR180711 rapidly penetrates into the brain (ID50=8 mg/kg p.o.). In functional studies performed with human α7 n-AChRs expressed in Xenopus oocytes or GH4C1 cells, the compound shows partial agonist effects (intrinsic activity=51 and 36%, EC50=4.4 and 0.9 μM, respectively). In rat cultured hippocampal neurons, SSR180711 induced large GABA-mediated inhibitory postsynaptic currents and small α-bungarotoxin sensitive currents through the activation of presynaptic and somato-dendritic α7 n-AChRs, respectively. In mouse hippocampal slices, the compound increased the amplitude of both glutamatergic (EPSCs) and GABAergic (IPSCs) postsynaptic currents evoked in CA1 pyramidal cells. In rat and mouse hippocampal slices, a concentration of 0.3 μM of SSR180711 increased long-term potentiation (LTP) in the CA1 field. Null mutation of the α7 n-AChR gene totally abolished SSR180711-induced modulation of EPSCs, IPSCs and LTP in mice. Intravenous administration of SSR180711 strongly increased the firing rate of single ventral pallidum neurons, extracellularly recorded in anesthetized rats. In microdialysis experiments, administration of the compound (3–10 mg/kg i.p.) dose-dependently increased extracellular acetylcholine (ACh) levels in the hippocampus and prefrontal cortex of freely moving rats. Together, these results demonstrate that SSR180711 is a selective and partial agonist at human, rat and mouse α7 n-AChRs, increasing glutamatergic neurotransmission, ACh release and LTP in the hippocampus.
Bruno Biton - One of the best experts on this subject based on the ideXlab platform.
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SSR180711, a Novel Selective α7 Nicotinic Receptor Partial Agonist: (1) Binding and Functional Profile
Neuropsychopharmacology, 2007Co-Authors: Bruno Biton, Olivier E Bergis, Frédéric Galli, Alain Nedelec, Alistair W Lochead, Samir Jegham, Danielle Godet, Christophe Lanneau, Raphaël Santamaria, Françoise ChesneyAbstract:In this paper, we report on the pharmacological and functional profile of SSR180711 (1,4-Diazabicyclo[3.2.2]nonane-4-carboxylic acid, 4-bromophenyl ester), a new selective α 7 acetylcholine Nicotinic Receptor (n-AChRs) partial agonist. SSR180711 displays high affinity for rat and human α 7 n-AChRs ( K _i of 22±4 and 14±1 nM, respectively). Ex vivo ^3[H] α -bungarotoxin binding experiments demonstrate that SSR180711 rapidly penetrates into the brain (ID_50=8 mg/kg p.o.). In functional studies performed with human α 7 n-AChRs expressed in Xenopus oocytes or GH4C1 cells, the compound shows partial agonist effects (intrinsic activity=51 and 36%, EC_50=4.4 and 0.9 μM, respectively). In rat cultured hippocampal neurons, SSR180711 induced large GABA-mediated inhibitory postsynaptic currents and small α -bungarotoxin sensitive currents through the activation of presynaptic and somato-dendritic α 7 n-AChRs, respectively. In mouse hippocampal slices, the compound increased the amplitude of both glutamatergic (EPSCs) and GABAergic (IPSCs) postsynaptic currents evoked in CA1 pyramidal cells. In rat and mouse hippocampal slices, a concentration of 0.3 μM of SSR180711 increased long-term potentiation (LTP) in the CA1 field. Null mutation of the α 7 n-AChR gene totally abolished SSR180711-induced modulation of EPSCs, IPSCs and LTP in mice. Intravenous administration of SSR180711 strongly increased the firing rate of single ventral pallidum neurons, extracellularly recorded in anesthetized rats. In microdialysis experiments, administration of the compound (3–10 mg/kg i.p.) dose-dependently increased extracellular acetylcholine (ACh) levels in the hippocampus and prefrontal cortex of freely moving rats. Together, these results demonstrate that SSR180711 is a selective and partial agonist at human, rat and mouse α 7 n-AChRs, increasing glutamatergic neurotransmission, ACh release and LTP in the hippocampus.
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SSR180711, a Novel Selective α7 Nicotinic Receptor Partial Agonist: (1) Binding and Functional Profile
Neuropsychopharmacology, 2007Co-Authors: Bruno Biton, Olivier E Bergis, Frédéric Galli, Alain Nedelec, Alistair W Lochead, Samir Jegham, Danielle Godet, Christophe Lanneau, Raphaël Santamaria, Françoise ChesneyAbstract:In this paper, we report on the pharmacological and functional profile of SSR180711 (1,4-Diazabicyclo[3.2.2]nonane-4-carboxylic acid, 4-bromophenyl ester), a new selective α 7 acetylcholine Nicotinic Receptor (n-AChRs) partial agonist. SSR180711 displays high affinity for rat and human α 7 n-AChRs ( K _i of 22±4 and 14±1 nM, respectively). Ex vivo ^3[H] α -bungarotoxin binding experiments demonstrate that SSR180711 rapidly penetrates into the brain (ID_50=8 mg/kg p.o.). In functional studies performed with human α 7 n-AChRs expressed in Xenopus oocytes or GH4C1 cells, the compound shows partial agonist effects (intrinsic activity=51 and 36%, EC_50=4.4 and 0.9 μM, respectively). In rat cultured hippocampal neurons, SSR180711 induced large GABA-mediated inhibitory postsynaptic currents and small α -bungarotoxin sensitive currents through the activation of presynaptic and somato-dendritic α 7 n-AChRs, respectively. In mouse hippocampal slices, the compound increased the amplitude of both glutamatergic (EPSCs) and GABAergic (IPSCs) postsynaptic currents evoked in CA1 pyramidal cells. In rat and mouse hippocampal slices, a concentration of 0.3 μM of SSR180711 increased long-term potentiation (LTP) in the CA1 field. Null mutation of the α 7 n-AChR gene totally abolished SSR180711-induced modulation of EPSCs, IPSCs and LTP in mice. Intravenous administration of SSR180711 strongly increased the firing rate of single ventral pallidum neurons, extracellularly recorded in anesthetized rats. In microdialysis experiments, administration of the compound (3–10 mg/kg i.p.) dose-dependently increased extracellular acetylcholine (ACh) levels in the hippocampus and prefrontal cortex of freely moving rats. Together, these results demonstrate that SSR180711 is a selective and partial agonist at human, rat and mouse α 7 n-AChRs, increasing glutamatergic neurotransmission, ACh release and LTP in the hippocampus.
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ssr180711 a novel selective α 7 Nicotinic Receptor partial agonist 1 binding and functional profile
Neuropsychopharmacology, 2007Co-Authors: Bruno Biton, Olivier E Bergis, Frédéric Galli, Alain Nedelec, Alistair W Lochead, Samir Jegham, Danielle Godet, Christophe Lanneau, Raphaël Santamaria, Françoise ChesneyAbstract:In this paper, we report on the pharmacological and functional profile of SSR180711 (1,4-Diazabicyclo[3.2.2]nonane-4-carboxylic acid, 4-bromophenyl ester), a new selective α7 acetylcholine Nicotinic Receptor (n-AChRs) partial agonist. SSR180711 displays high affinity for rat and human α7 n-AChRs (Ki of 22±4 and 14±1 nM, respectively). Ex vivo 3[H]α-bungarotoxin binding experiments demonstrate that SSR180711 rapidly penetrates into the brain (ID50=8 mg/kg p.o.). In functional studies performed with human α7 n-AChRs expressed in Xenopus oocytes or GH4C1 cells, the compound shows partial agonist effects (intrinsic activity=51 and 36%, EC50=4.4 and 0.9 μM, respectively). In rat cultured hippocampal neurons, SSR180711 induced large GABA-mediated inhibitory postsynaptic currents and small α-bungarotoxin sensitive currents through the activation of presynaptic and somato-dendritic α7 n-AChRs, respectively. In mouse hippocampal slices, the compound increased the amplitude of both glutamatergic (EPSCs) and GABAergic (IPSCs) postsynaptic currents evoked in CA1 pyramidal cells. In rat and mouse hippocampal slices, a concentration of 0.3 μM of SSR180711 increased long-term potentiation (LTP) in the CA1 field. Null mutation of the α7 n-AChR gene totally abolished SSR180711-induced modulation of EPSCs, IPSCs and LTP in mice. Intravenous administration of SSR180711 strongly increased the firing rate of single ventral pallidum neurons, extracellularly recorded in anesthetized rats. In microdialysis experiments, administration of the compound (3–10 mg/kg i.p.) dose-dependently increased extracellular acetylcholine (ACh) levels in the hippocampus and prefrontal cortex of freely moving rats. Together, these results demonstrate that SSR180711 is a selective and partial agonist at human, rat and mouse α7 n-AChRs, increasing glutamatergic neurotransmission, ACh release and LTP in the hippocampus.
Robert Freedman - One of the best experts on this subject based on the ideXlab platform.
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Sensory gating and alpha-7 Nicotinic Receptor gene allelic variants in schizoaffective disorder, bipolar type.
American Journal of Medical Genetics, 2006Co-Authors: Laura F Martin, Sherry Leonard, Robert Freedman, Mei-hua Hall, Jason R Tregellas, Ann OlincyAbstract:Objectives: Single nucleotide allelic variants in the promoter region of the chromosome 15 alpha-7 acetylcholine Nicotinic Receptor gene (CHRNA7) are associated with both schizophrenia and the P50 auditory evoked potential sensory gating deficit. The purpose of this study was to determine if CHRNA7 promoter allelic variants are also associated with abnormal P50 ratios in persons with schizoaffective disorder, bipolar type. Methods: P50 auditory evoked potentials were recorded in a paired stimulus paradigm in 17 subjects with schizoaffective disorder, bipolar type. The P50 test to conditioning ratio was used as the measure of sensory gating. Mutation screening of the CHRNA7 promoter region was performed on the subjects’ DNA samples. Comparisons to previously obtained data from persons with schizophrenia and controls were made. Results: Subjects with schizophrenia, regardless of allele status, had an abnormal mean P50 ratio. Subjects with schizoaffective disorder, bipolar type and a variant allele had an abnormal mean P50 ratio, whereas those schizoaffective subjects with the common alleles had a normal mean P50 ratio. Normal control subjects had a normal mean ratio, but controls with variant alleles had higher P50 ratios. Conclusions: In persons with bipolar type schizoaffective disorder, CHRNA7 promoter region allelic variants are linked to the capacity to inhibit the P50 auditory evoked potential and thus are associated with a type of illness genetically and biologically more similar to schizophrenia. 2006 Wiley-Liss, Inc.
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Alpha-7 Nicotinic Receptor agonists: potential new candidates for the treatment of schizophrenia
Psychopharmacology, 2004Co-Authors: Laura F Martin, Robert FreedmanAbstract:Rationale and objective Auditory sensory gating, a biological measurement of the ability to suppress the evoked response to the second of two auditory stimuli, is diminished in people with schizophrenia. Deficits in sensory gating are associated with attentional impairment, and may contribute to cognitive symptoms and perceptual disturbances. This inhibitory process, which involves the alpha_7 Nicotinic Receptor mediated release of gamma-aminobutyric acid (GABA) by hippocampal interneurons, represents a potential new target for therapeutic intervention in schizophrenia. Method This paper will review several lines of evidence implicating the Nicotinic-cholinergic, and specifically, the alpha_7 Nicotinic Receptor system in the pathology of schizophrenia and the evidence that alpha_7 Nicotinic Receptor agonists may ameliorate some of these deficits. Results Impaired auditory sensory gating has been linked to the alpha_7 Nicotinic Receptor gene on the chromosome 15q14 locus. Single nucleotide polymorphisms of the promoter region of this gene are more frequent in people with schizophrenia. Although nicotine can acutely reverse diminished auditory sensory gating in people with schizophrenia, this effect is lost on a chronic basis due to Receptor desensitization. Clozapine is able to reverse auditory sensory gating impairment, probably through an alpha_7 Nicotinic Receptor mechanism, in both humans and animal models with repeated dosing. The alpha_7 Nicotinic agonist 3-2,4 dimethoxybenzylidene anabaseine (DMXBA) can also enhance auditory sensory gating in animal models. DMXBA is well tolerated in humans and improves several cognitive measures. Conclusion Alpha-7 Nicotinic Receptor agonists appear to be reasonable candidates for the treatment of cognitive and perceptual disturbances in schizophrenia.
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alpha 7 Nicotinic Receptor agonists potential new candidates for the treatment of schizophrenia
Psychopharmacology, 2004Co-Authors: Laura F Martin, William R Kem, Robert FreedmanAbstract:Rationale and objective Auditory sensory gating, a biological measurement of the ability to suppress the evoked response to the second of two auditory stimuli, is diminished in people with schizophrenia. Deficits in sensory gating are associated with attentional impairment, and may contribute to cognitive symptoms and perceptual disturbances. This inhibitory process, which involves the alpha7 Nicotinic Receptor mediated release of gamma-aminobutyric acid (GABA) by hippocampal interneurons, represents a potential new target for therapeutic intervention in schizophrenia.
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Nicotinic Receptor desensitization and sensory gating deficits in schizophrenia
Biological Psychiatry, 1998Co-Authors: Jay M. Griffith, Jaishri E Oneill, Frederick Petty, David L Garver, David A Young, Robert FreedmanAbstract:Abstract Background: Nicotinic Receptor dysfunction is a possible mechanism of the abnormal sensory gating observed in schizophrenia with the P50 auditory event-related potential. Although Nicotinic Receptors normally desensitize after activation by acetylcholine or nicotine, pathologically increased desensitization might cause Receptor dysfunction in schizophrenia. To examine this possibility, central cholinergic neuronal activity was diminished by allowing schizophrenic patients to sleep briefly, after which they experienced a transient period of normal P50 gating, consistent with Receptor resensitization during the absence of cholinergic stimulation. A critical test of the mechanism is whether this resensitization is blocked by concurrent administration of nicotine, which would provide continuous Receptor stimulation. Methods: Six schizophrenic patients repeated the sleep experiment during nicotine exposure from a dermal patch, in a double-blind, placebo-controlled design. Results: The normalization of P50 gating immediately postsleep was replicated in the placebo arm, but this effect was decreased in all six patients during exposure to nicotine. Conclusions: The results suggest that Nicotinic Receptor desensitization is responsible for the loss of P50 gating in schizophrenia.
Carol B Fox - One of the best experts on this subject based on the ideXlab platform.
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3 5 bicyclic aryl piperidines a novel class of α4β2 neuronal Nicotinic Receptor partial agonists for smoking cessation
Bioorganic & Medicinal Chemistry Letters, 2005Co-Authors: Jotham Wadsworth Coe, Paige R Brooks, Michael C Wirtz, Crystal G Bashore, Krista E Bianco, Michael G Vetelino, Eric P Arnold, Lorraine A Lebel, Carol B Fox, David F TingleyAbstract:3,5-Bicyclic aryl piperidines are a new class of high-affinity α4β2 Nicotinic Receptor agents. We have sought Nicotinic Receptor partial agonists of the α4β2 Nicotinic acetylcholine Receptor for smoking cessation, and a number of compounds fulfill potency, selectivity, and efficacy requirements in vitro. In vivo, selected agents demonstrate potent partial agonist efficacy on the mesolimbic dopamine system, a key measure of therapeutic potential for smoking cessation.
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varenicline an α4β2 Nicotinic Receptor partial agonist for smoking cessation
Journal of Medicinal Chemistry, 2005Co-Authors: Jotham Wadsworth Coe, Paige R Brooks, Michael C Wirtz, Michael G Vetelino, Eric P Arnold, Lorraine A Lebel, Jianhua Huang, Steven B Sands, Thomas I Davis, Carol B FoxAbstract:Herein we describe a novel series of compounds from which varenicline (1, 6,7,8,9-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine) has been identified for smoking cessation. Neuronal Nicotinic acetylcholine Receptors (nAChRs) mediate the dependence-producing effects of nicotine. We have pursued α4β2 Nicotinic Receptor partial agonists to inhibit dopaminergic activation produced by smoking while simultaneously providing relief from the craving and withdrawal syndrome that accompanies cessation attempts. Varenicline displays high α4β2 nAChR affinity and the desired in vivo dopaminergic profile.
